Perioperative Durvalumab Regimen Upholds EFS Benefit in Resectable NSCLC

John V. Heymach, MD, PhD

A perioperative regimen of neoadjuvant durvalumab (Imfinzi) plus chemotherapy, followed by surgery and adjuvant durvalumab, continued to showcase an improvement in event-free survival (EFS) compared with neoadjuvant placebo plus chemotherapy, followed by surgery and adjuvant placebo in patients with treatment-naive stage IIA to IIIB (N2) resectable non–small cell lung cancer (NSCLC), according to longer follow-up from the phase 3 AEGEAN trial (NCT03800134) that was presented during the 2024 IASLC World Conference on Lung Cancer.¹

Results showed that, at the second planned interim analysis in the modified intention-to-treat (mITT) population, the median EFS was not reached (NR; 95% CI, 42.3-NR) with the durvalumab regimen (n = 366) compared with 30.0 months (95% CI, 20.6-NR) with the placebo regimen (n = 374; HR, 0.69; 95% CI, 0.55-0.88) at a median follow-up in censored patients of 25.9 months (range, 0.0-58.6). The 3-year EFS rates were 60.1% and 47.9%, respectively.

“These updated data further support FDA-approved perioperative durvalumab as a new treatment option for patients with resectable NSCLC,” lead study author John V. Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology and David Bruton Endowed Chair in Cancer Research at The University of Texas MD Anderson Cancer Center, said in an oral presentation of these findings.

Previous data of the phase 3 AEGEAN trial showed that the combination of perioperative durvalumab plus neoadjuvant chemotherapy significantly improved EFS (HR, 0.68; 95% CI, 0.53-0.88; P = .004) and a 13.0% difference in pathologic complete response (pCR; 95% CI, 8.7%-17.6%; P <.001) compared with neoadjuvant chemotherapy alone, along with an acceptable safety profile.

In August 2024, the FDA approved durvalumab combined with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after surgery, for adult patients with resectable (tumors ≥4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements.2 The approval was based on the first interim analysis of the AEGEAN data that had approximately 23% of patients on adjuvant therapy and median EFS follow-up of 11.7 months.³

At the 2024 IASLC World Conference on Lung Cancer, Heymach presented updated EFS results from the second interim analysis, which was at 39.1% maturity. The data cutoff date was May 10, 2024.

In AEGEAN, 802 patients were randomized 1:1 to receive neoadjuvant intravenous (IV) durvalumab at 1500 mg plus platinum-based chemotherapy every 3 weeks for 4 cycles or IV placebo plus platinum-based chemotherapy every 3 weeks for 4 cycles. Following surgery, patients either received adjuvant durvalumab or placebo at 1500 mg every 4 weeks for 12 cycles.

To be eligible for enrollment, patients had to have treatment-naive stage IIA to IIIB (N2) resectable NSCLC as per AJCC 8th edition criteria; have an ECOG performance status of 0 or 1; have planned surgery with lobectomy, sleeve resection, or bilobectomy; confirmed PD-L1 status; and no documented EGFR/ALK aberrations.

Stratification factors included disease stage (II vs III) and PD-L1 expression (≥1% vs <1%). Efficacy analyses were conducted in the mITT population, which excluded those with EGFR/ALK aberrations.

The primary end points were centrally evaluated pCR (IASLC 2020) and EFS via blinded independent central review (BICR) and RECIST v1.1 criteria. Key secondary outcome measures were evaluated centrally major pathologic response, disease-free survival (DFS) DFS via BICR in the resected subpopulation, and overall survival (OS).

Baseline characteristics were similar between the 2 arms. Heymach noted that the resected subpopulation for DFS, which comprised those with R0/R1 margins and no evidence of disease progression in their first scan after surgery, had baseline characteristics that were similar to the overall mITT population.

In the durvalumab arm and placebo arm, the median age was 65.0 years (range, 30-88), with 12.0% and 9.6% of patients, respectively, aged 75 years or older. A total 68.9% and 74.3% of patients were male, and 68.6% and 68.2% had an ECOG performance status of 0. Most patients were White (56.3% vs 51.1%) and were from Asia (38.8% vs 43.6%) and Europe (38.5% vs 37.4%), as well as former smokers (60.1% vs 59.6%). In the durvalumab arm, patients had stage II (28.4%), IIIA (47.3%), or IIIB disease (24.0%); these rates were 29.4%, 44.1%, and 26.2% in the placebo arm. A total 46.2% and 51.1% of patients on durvalumab and placebo, respectively, had squamous disease. PD-L1 expression was less than 1% on tumor cells in 33.3% and 33.4% of patients, between 1% and 49% in 36.9% and 38.0%, and 50% or greater in 29.8% and 28.6% of patients, respectively. The neoadjuvant chemotherapy used was carboplatin based in 72.7% and 74.3% of patients.

No patients remained on treatment at the second interim EFS analysis. A total 68.6% of patients completed all adjuvant durvalumab therapy vs 63.7% of those who received all adjuvant placebo. Patients discontinued adjuvant treatment due to progressive disease (durvalumab, 14.9% vs placebo, 29.5%), adverse effects (11.2% vs 4.6%, respectively), patient decision (3.7% vs 1.7%), other (0.8% vs 0.4%), or death (0.8% vs 0%).

Additional results showed that the EFS benefit with durvalumab was upheld across all prespecified subgroups. Heymach noted that those with squamous histology had a median EFS of NR (95% CI, 41.2-NR) with durvalumab vs 40.4 months (95% CI, 15.1-NR) with placebo (HR, 0.70; 95% CI, 0.49-0.98). In those with nonsquamous disease, the median EFS was also NR (95% CI 36.6-NR) vs 28.6 months (95% CI, 19.8-NR), respectively (HR, 0.73; 95% CI, 0.53-1.00).

“You can see that EFS benefit was maintained across major study subgroups, particularly for squamous vs nonsquamous histology across disease stages, and single vs multi-station lymph node disease and across PD-L1 levels,” Heymach explained.

The EFS benefit with durvalumab was maintained irrespective of the planned neoadjuvant platinum agent. For those who received cisplatin, the median EFS with durvalumab (n = 100) was NR (95% CI, NR-NR) compared with those on placebo who received cisplatin (n = 96; 95% CI, 13.9-NR), leading to a hazard ratio of 0.58 (95% CI, 0.35-0.93). Here, the 3-year EFS rates were 64.6% and 51.3%, respectively. In the carboplatin arm for durvalumab (n = 266) and placebo (n = 278), the median EFS was NR (95% CI, 36.6-NR) and 25.2 months (95% CI, 20.6-NR), respectively (HR, 0.75; 95% CI, 0.57-0.97). The 3-year EFS rates were 58.5% and 46.1%, respectively.

Exploratory analysis data also showed that the EFS improvement was more pronounced in those who received adjuvant therapy (durvalumab, n = 242; placebo, n = 237) compared with those who did not receive adjuvant therapy. In the adjuvant therapy arm, the median EFS was NR (95% CI, NR-NR) with durvalumab and NR with placebo (95% CI, 42.6-NR), with a HR of 0.62 (95% CI, 0.44-0.86). The 3-year EFS rates were 72.8% vs 61.6%, respectively. In those who did not receive adjuvant therapy (neoadjuvant durvalumab, n = 124; placebo, n = 137), the median EFS was 5.1 months (95% CI, 4.5-9.3) vs 5.2 months (95% CI, 4.1-6.3) in the durvalumab and placebo arms, respectively. The 3-year EFS rates were 28.7% vs 16.5%, respectively.

“Note that these [data] are based on a post-randomization variable. So as always, [they] should be viewed with caution,” Heymach added.

Another exploratory analysis evaluated EFS by pCR status, demonstrating that the EFS was higher with durvalumab irrespective of whether patients demonstrated a pCR. In those who did achieve a pCR on durvalumab (n = 63), the median EFS was NR (95% CI, NR-NR) compared with NR (95% CI, 25.4-NR) with placebo (n = 16; HR, 0.73; 95% CI, 0.22-3.28). The 3-year pCR rates were 86.3% vs 78.3%, respectively. For patients without a pCR, the median EFS with durvalumab (n = 303) was 41.2 months (95% CI, 31.9-NR) compared with 25.9 months (95% CI, 19.3-45.0) for placebo (n = 358; HR, 0.83; 95% CI, 0.64-1.03). The 3-year EFS rates were 53.2% vs 46.4%, respectively.

DFS was also measured in the modified resected subpopulation for the durvalumab (n = 242) and placebo arms (n = 231), in which the median DFS was NR (95% CI, NR-NR) and NR (95% CI, 41.5-NR), respectively (HR, 0.66; 95% CI, 0.47-0.92; P = .0137) at a median follow-up of 27.3 months (95% CI, 0.8-55.7). The 3-year DFS rates were 71.2% and 61.4%, respectively.

Furthermore, in patients who achieved a pCR and received durvalumab (n = 55), the median DFS was NR (95% CI, NR-NR) and was NR (95% CI, 10.5-NR) with placebo (n = 13; unstratified HR, 0.31; 95% CI, 0.07-1.51). The 3-year DFS rates were 91.6% with durvalumab vs 69.9% with placebo. In those who did not achieve a pCR and received durvalumab (n = 187) and placebo (n = 218), the median DFS was NR (95% CI, NR-NR) vs NR (95% CI, 41.5-NR), respectively (unstratified HR, 0.82; 95% CI, 0.58-1.15). The 3-year DFS rates were 64.1% and 60.8%, respectively.

At 35% maturity, there was a trend in OS favoring durvalumab with a median OS of NR (95% CI, NR-NR) with durvalumab vs 53.2 months (95% CI, 44.3-NR) with placebo (HR, 0.89; 95% CI, 0.70-1.14). The median follow-up was 33.6 months (range, 0.7-64.3); the 3-year OS rates were 67.1% vs 63.9%.

“The study was conducted at the height of the COVID-19 pandemic, at which time, we did not have yet effective vaccines,” Heymach said. “There was a preplanned analysis censoring patients that died from COVID-19, and for that group, there is a further reduction in the OS hazard ratio at 0.84.”

Additionally, lung cancer–specific survival (LCSS) was evaluated in an exploratory analysis in the mITT population. The median LCSS was NR (95% CI, NR-NR) with durvalumab and with placebo (95% CI, 48.3-NR; HR, 0.70; 95% CI, 0.52-0.93). The 3-year LCSS rates were 76.7% vs 68.9%, respectively.

Regarding safety in the overall study period (which comprised neoadjuvant, surgical, and adjuvant treatment phases), any-grade all-causality adverse effects (AEs) occurred in 96.5% and 95.2% of durvalumab- (n = 401) and placebo-treated patients (n = 398), respectively; grade 3/4 AEs occurred in 43.6% and 43.2%, respectively. Serious AEs occurred in 39.2% and 31.7% of patients. There were 23 deaths on the durvalumab arm vs 15 on the placebo arm; AEs that led to treatment discontinuation occurred in 12.7% of those on durvalumab vs 6.3% of those on placebo; AEs that led to surgery cancellation occurred in 1.7% and 1.0% of patients, respectively.

All-grade AEs potentially related to treatment occurred in 87.3% and 81.7% of durvalumab- and placebo-treated patients, respectively; grade 3/4 AEs were reported in 33.4% of patients in both arms and 7 patients and 2 patients died, respectively. Any-grade immune-mediated AEs occurred in 25.4% of patients on durvalumab vs 10.3% of those on placebo; 4.5% and 2.5% of AEs were grade 3/4, respectively. Any-grade pneumonitis occurred in 4.5% and 1.8% of patients, respectively.

In the adjuvant study period of durvalumab- (n = 266) and placebo-treated patients (n = 254), any-grade all causality AEs occurred in 84.2% and 76.8% of patients, respectively, with 15.4% and 10.6% of AEs being grade 3/4. Serious AEs occurred in 15.4% and 10.2% of patients, and 4 and 2 patients died in each arm, respectively. There were 9.8% and 3.9% cases of treatment discontinuation with durvalumab and placebo, respectively.

Any-grade potentially treatment-related AEs occurred in 49.2% and 29.9% of durvalumab- and placebo-treated patients, respectively, with 7.5% and 3.5% being of grade 3/4. One patient died in each arm. Finally, any-grade immune-mediated AEs occurred in 22.9% and 8.3% of patients on the durvalumab and placebo arms, 2.3% and 1.6% of which were grade 3/4. Any-grade pneumonitis occurred in 3.4% and 2.0% of patients, respectively.

References

1. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable NSCLC (R-NSCLC): updated outcomes from the phase 3 AEGEAN trial. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA13.03.
2. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed September 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer
3. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875